This invention relates to novel compounds and compositions for use in terminating a pregnancy of a higher female primate having a defined menstrual or estrus cycle. The method of use is by administration to the pregnant female of a contragestative agent, which has estrogen sulfotransferase inhibitory activity and which prevents implantation of the blastocyst or fertilized egg. Further, the invention relates to novel processes having intermediates for synthesizing the novel compounds.
Compositions for use as estrogen sulfotransferase inhibitors are disclosed in U.S. Pat. No. 4,340,602. Such estrogen sulfotransferase inhibition provides highly effective contragestative agents for higher primates having a well defined menstrual or estrus cycle. Particularly such estrogen sulfotransferase agents are administered to a female patient who suspects that she is in the early stages of pregnancy. These agents are therefore effective for terminating pregnancies at a very early stage with minimal exposure of the patient to powerful steroidal medication. Additionally, unlike the widely used "pill", formulations which must be administered in anticipation of coitus, the compounds used in the method of the present invention are administered only when needed and then only for a relatively short time before or at the expected time of implantation.
It is shown by Rozhin et al, J. Biol Chem., 1977, 252, 7214, that 4-nitroestrone 3-0-methylether blocks estrogen sulfurylation without interfering with the receptor binding and nuclear migration of physiological levels of 17.beta.-estradiol. However, Rozhin et al does not teach prevention of blastocyst implantation.
Further, the novel compounds of the present invention are not taught by the disclosure in either U.S. Pat. No. 4,340,602 or Rozhin et al.
The compounds within the scope of Formula T used as reactants to provide intermediates in the present invention are disclosed by Musliner et al, "The Replacement of Phenolic Hydroxyl Groups by Hydrogen", J. Am. Chem. Soc. 88:18, pp. 4271-3 (Sept. 20, 1966) for hydrogenolysis of various phenolic ethers. However, Musliner et al contains no teaching that would make obvious its use for the conversion of the substituted estrones within the present invention. Preparation of phenyl trifluoromethanesulfonate is shown by Yagupol'skii et al, "Aryl Trifluoromethanesulfoantes", Institute of Organic Chemistry, Academy of Sciences of the Ukranian SSR. Translated from Zhurnal Organicheskoi Khimii Vol. 7, No. 5, pp. 996-1001, May, 1971. Further, the hydrogenolysis of phenol or enols using perfluorosulfonates is shown by L. R. Subramanian et al, "Perfluoroalkane Sulfonic Esters, Methods of Preparation and Applications in Organic Chemistry", Synthesis, 85-125 (1982).
Replacement of an amino group at the 3-position of selected steroidal compounds by a fluoro is shown in Morrow et al, "The Trienes", J. Med. Chem. 1966, Vol. 9, pp. 249-51. Again, the teaching is limited so as to fail to teach the present invention.
As used in the specification and claims, "higher primate" includes those primate species in which the female generally has a predictable menstrual or estrus cycle. These species include the human, rhesus monkey, orangutang, chimpanzee, etc.
The method of the present invention may be used for other mammalian species including bovine and porcine animals.
Pregnancy is a condition of the female mammal in which a fertilized ovum is contained in her reproductive tract. For the purpose of this invention, the period of gestation or pregnancy is defined as beginning at the point of fertilization.
Nidation as used in the specification and claims, means the period of time in which the fertilized egg (blastocyst) attaches itself and penetrates within the epithelial lining of the uterus.
Implantation as used in the specification and claims means the period of time in which the blastocyst begins to form a placental membrane and to establish a direct connection with the blood supply of the mother. Although the exact process by which the active material is employed in the practice of this invention in terminating a pregnancy is unclear, it appears that the method of this invention interferes with the implantation process by decreasing the ability of the mother to support the life of the blastocyst. Thus, the gestation period is interrupted at a very early stage. Therefore, the method of this invention is to be considered as a method of preventing implantation or of contragestation, rather than as a method of abortion.
Particularly this invention relates to novel compounds for terminating a pregnancy comprising preventing implantation of a blastocyst in the epithelial uterine lining of a pregnant female by administration to the pregnant female during the period of implantation an amount of the compound effective to prevent implantation.